BrUOG 387: Phase Ib investigator-initiated trial of a heat shock protein 90 inhibitor (HSP90i) combined with a CDK4/6i in advanced breast cancer progressing on CDK4/6i and in solid tumors with retinoblastoma (Rb)-deficiency (IND163592).
Authors: Wafik S. El-Deiry, Stephanie L. Graff, Christopher G. Azzoli, Don S. Dizon, Mary Anne Fenton, William M. Sikov, Howard Safran, Hina Khan, Humera Khurshid, Andrew Schumacher, Lanlan Zhou, Shuai Zhao, Attila A. Seyhan, Dinara Ryspayeva, Roxanne Wood, Arthur Winer, Elizabeth Martine Calleja, Eric A. Ross
Journal: Journal of Clinical Oncology (2023)

TPS3167 Background: Cyclin-dependent kinases 4/6 (CDK4/6) promote cell-cycle progression and cancer growth. CDK4/6 inhibitors (CDK4/6i), in combination with hormonal therapy, increase progression-free and overall survival (PFS and OS) in breast cancer but resistance to CDK4/6i is associated with genomic abnormalities including Rb-deficiency. Combined CDK4/6i/HSP90i has been shown to inhibit HIF1-alpha including in tumor cells with Rb-deficiency. Synergy between multiple CDK4/6i’s and HSP90i’s has suggested a drug class effect for combination. In CDK4/6i-treated cells, E3-ubiquitin ligase Smurf2 associates with and targets degradation of HIF1-alpha independent of VHL or hypoxia. BrUOG 387 investigates whether dual targeting of CDK4/6 and HSP90, through HIF1-alpha in patients with ER/PR+ Her2- advanced breast cancer progressing on CDK4/6i and patients with refractory Rb-deficient tumors is safe and reasonably tolerated. Methods: A phase Ib open-label single-arm dose de-escalation study is evaluating safety, tolerability as primary outcomes, recommended doses for cohort expansion and preliminary efficacy of CDK4/6i and HSP90i (IND163592; NCT05655598; the only HSP90i combination study in US). Patients with ER/PR+ Her2- advanced breast cancer progressing on CDK4/6i, and in cohort expansion, patients with Rb-deficient solid tumors (SCLC, soft tissue sarcoma, endometrial and bladder cancer) are included. CDK4/6i (palbociclib at dose previously tolerated up to 125 mg daily PO D1-21 of 28 day cycle) in combination with HSP90i (TAS-116/pimitespib starting at 120 mg 5 days on 2 days off, for D1-28 of cycle) is used in 3+3 dose-de-escalation design. The study includes PK analysis, and PD analysis will include HIF1/2, Smurf2, Rb, HIF targets VEGF, erythropoietin, Glut1, proliferation, cell death, cancer stem cells, NK, T-cells, RNA-seq and angiogenesis in pre- and post-treatment biopsies. Biostatistical design and analysis includes 3 dose levels of TAS-116 + palbociclib (level 0: TAS-116 120 mg, palbociclib 125 mg; level -1: TAS-116 80 mg, palbociclib 125 mg); level -2: TAS-116 40 mg, palbociclib 125 mg). Limiting Toxicities will include grade 4 neutropenia lasting &gt; 7 days, neutropenic fever, grade 4 thrombocytopenia or Grade 3 non-hematologic toxicity not controlled with medical management. The study will enroll a total of approximately 15-27 patients (6-18 patients in dose de-escalation portion of the study and 9 additional patients in the cohort expansion phase). Secondary outcome analyses include response rate (CR, PR) measured by RECIST v.1.1 with exact two-sided 95% confidence intervals. OS, PFS, TTP, and DOR will be summarized using methods of Kaplan and Meier. Clinical trial information: NCT05655598 .